Self-Propulsion of Two Contacting Bubbles Due to the Radiation Interaction Force.

In this paper, we consider a new bubble-based microswimmer composed of two contacting bubbles. Under the action of an acoustic field, both bubbles are oscillating, and locomotion of the two-bubble system is observed. A theory is developed that allows one to calculate the acoustic radiation interaction forces between two gas bubbles in an incompressible viscous liquid for any small separation distance between the bubbles. This theory is used to demonstrate that two acoustically excited bubbles can create a self-propelled microswimmer due to a nonzero net force experienced by the bubbles when they come in contact. Experimental evidence of the creation of such a swimmer and of its motion is provided.

Acoustic microstreaming produced by nonspherical oscillations of a gas bubble. IV. Case of modes n and m.

This paper is the conclusion of work done in our previous papers [A. A. Doinikov et al., Phys. Rev. E 100, 033104 (2019)10.1103/PhysRevE.100.033104; Phys. Rev. E 100, 033105 (2019)10.1103/PhysRevE.100.033105]. The overall aim of the study is to develop a theory for modeling the velocity field of acoustic microstreaming produced by nonspherical oscillations of a gas bubble. In our previous papers, general equations were derived to describe the velocity field of acoustic microstreaming produced by modes m and n of bubble oscillations. Particular cases of mode interaction were derived, such as the 0-n, 1-1, 1-m, and n-n interactions. Here the general case of interaction between modes n and m, n>m, is solved analytically. Solutions are expressed in terms of complex mode amplitudes, meaning that the mode amplitudes are assumed to be known and serve as input data for the calculation of the velocity field of microstreaming. No restrictions are imposed on the ratio of the bubble radius to the viscous penetration depth. The n-m interaction results in specific streaming patterns: At large distance from the bubble interface the pattern exhibits 2|n-m| lobes, while 2min(m,n) lobes exist in the bubble vicinity. The spatial organization of the recirculation zones is unique for the interaction of two distinct nonspherical modes and therefore appears as a signature of the n-m interaction.

Secondary radiation force between two closely spaced acoustic bubbles.

Two acoustic bubbles may attract or repel due to the secondary radiation force acting on them. We use here a dual-frequency levitation chamber in order to trap two oscillating microbubbles at close, fixed distance, and to perform measurements of the interaction force. We successfully compare our measurements to a commonly used theoretical model that assumes linear spherical oscillations, and disregards attenuation and multiple scattering between bubbles. The deviation from the model arises when nonspherical surface oscillations are triggered, leading to an additional hydrodynamic force induced by second-order liquid flow.

A Single High-Intensity Shock Wave Pulse With Microbubbles Opens the Blood-Brain Barrier in Rats.

Focused extracorporeal shockwave (FSW), one kind of focused high-intensity pulsed ultrasound, has been shown to induce blood-brain barrier (BBB) opening in targeted brain areas in rat animal models with minimal detrimental effects below threshold intensity levels or iterations. In the current study, we found that the thresholds could be further reduced by the addition of microbubbles (ultrasound contrast agents or UCA; SonoVue). FSW with 2 × 106 MBs/kg of UCA (20% of clinical dosage) at an intensity level of 0.1 (peak positive pressure 5.4 MPa; peak negative pressure -4.2 MPa; energy flux density 0.03 mJ/mm2) resulting in a 100% BBB opening rate without detectable hemorrhage or apoptosis in the brain. Significantly reduced free radical production was found compared with 0.5 MHz focused ultrasound at a peak negative pressure of 0.44 MPa (1% duty cycle and 4 × 107 MBs/kg of UCA). FSW devices offer advantages of commercial availability and high safety, and thus may facilitate future research and applications of focal BBB opening for oncological and pharmacological purposes.

Acoustic microstreaming produced by nonspherical oscillations of a gas bubble. III. Case of self-interacting modes n-n.

This paper is the continuation of work done in our previous papers [A. A. Doinikov et al., Phys. Rev. E 100, 033104 (2019)2470-004510.1103/PhysRevE.100.033104; Phys. Rev. E 100, 033105 (2019)].2470-004510.1103/PhysRevE.100.033105 The overall aim of the study is to develop a theory for modeling the velocity field of acoustic microstreaming produced by nonspherical oscillations of an acoustically driven gas bubble. In our previous papers, general equations have been derived to describe the velocity field of acoustic microstreaming produced by modes m and n of bubble oscillations. After solving these general equations for some particular cases of modal interactions (cases 0-n, 1-1, and 1-m), in this paper the general equations are solved analytically for the case that acoustic microstreaming results from the self-interaction of an arbitrary surface mode n≥1. Solutions are expressed in terms of complex mode amplitudes, meaning that the mode amplitudes are assumed to be known and serve as input data for the calculation of the velocity field of acoustic microstreaming. No restrictions are imposed on the ratio of the bubble radius to the viscous penetration depth. The self-interaction results in specific streaming patterns: a large-scale cross pattern and small recirculation zones in the vicinity of the bubble interface. Particularly the spatial organization of the recirculation zones is unique for a given surface mode and therefore appears as a signature of the n-n interaction. Experimental streaming patterns related to this interaction are obtained and good agreement is observed with the theoretical model.

Acoustic microstreaming produced by nonspherical oscillations of a gas bubble. I. Case of modes 0 and m.

A theory is developed that allows one to model the velocity field of acoustic microstreaming produced by nonspherical oscillations of an acoustically driven gas bubble. It is assumed that some of the bubble oscillation modes are excited parametrically and hence can oscillate at frequencies different from the driving frequency. Analytical solutions are derived in terms of complex amplitudes of oscillation modes, which means that the mode amplitudes are assumed to be known and serve as input data when the velocity field of acoustic microstreaming is calculated. No restrictions are imposed on the ratio of the bubble radius to the viscous penetration depth. The present paper is the first part of our study in which a general theory is developed and then applied to the case that acoustic microstreaming is generated by the interaction of the breathing mode (mode 0) with a mode of arbitrary order m≥1. Examples of numerical simulations and a comparison with experimental results are provided.

Acoustic microstreaming produced by nonspherical oscillations of a gas bubble. II. Case of modes 1 and m.

This paper continues a study that was started in our previous paper [A. A. Doinikov et al., Phys. Rev. E 100, 033104 (2019)10.1103/PhysRevE.100.033104]. The overall aim of the study is to develop a theory for modeling the velocity field of acoustic microstreaming produced by nonspherical oscillations of an acoustically driven gas bubble. In the previous paper, general equations were derived that describe the velocity field of acoustic microstreaming produced by modes n and m of bubble oscillations. In the present paper, the above equations are solved analytically in the case that acoustic microstreaming is the result of the interaction of the translational mode (mode 1) with a mode of arbitrary order m≥1. Solutions are expressed in terms of complex mode amplitudes, which means that the mode amplitudes are assumed to be known and serve as input data for the calculation of the velocity field of acoustic microstreaming. No restrictions are imposed on the ratio of the bubble radius to the viscous penetration depth. Analytical results are illustrated by numerical examples.

Accompanying the frequency shift of the nonlinear resonance of a gas bubble using a dual-frequency excitation.

An asymptotic method is applied to analyze the nonlinear oscillations of a gas bubble driven by a dual-frequency excitation. More specifically, the latter is considered as a combination of two neighboring, incommensurate frequencies and is treated as a nonstationary excitation. This implies that both amplitude and phase of the bubble response are slowly oscillating at the time scale of the frequency difference, thus leading to a regime of aperiodic oscillations. The approximate solution is successfully compared with numerical simulations and reveals the possibility of achieving larger bubble response amplitude compared to the monofrequency excitation for sufficiently high driving pressure and specific values of the frequency difference. The asymptotic theory captures the generation of additional spectral components coming from the nonlinear mixing of both driving frequencies. This mechanism is responsible for a global enhancement of the dual-frequency bubble response as it enables an energy transfer towards more efficient components which are successively tuned with the nonlinearly shifted resonance frequency of the bubble, thus limiting the saturation due to softening.

Ultrasound enhanced PEI-mediated gene delivery through increasing the intracellular calcium level and PKC-δ protein expression.

PURPOSE: Polyethylenimine (PEI), a cationic polymer, has been shown to aggregate plasmid DNA and facilitate its internalization. It has also been shown that combining ultrasound (US) with PEI could enhance and prolong in vitro and in vivo transgene expression. However, the role US in the enhancement of PEI uptake is poorly understood. This study investigates the impact of US on PEI-mediated gene transfection. METHODS: Specific endocytosis pathway siRNA, including clathrin HC siRNA, caveolin-1 siRNA and protein kinase C-delta (PKC-δ) siRNA, are used to block the corresponding endocytosis pathways prior to the transfection of luciferase DNA/PEI polyplexes to cultured cells by 1-MHz pulsed US with ultrasound contrast agent SonoVue®. RESULTS: Transgene expression was found not to be enhanced by US treatment in the presence of the PKC-δ siRNA. We further demonstrated that PKC-δ protein could be enhanced at 6 h after US exposure. Moreover, intracellular calcium levels were found to be significantly increased at 3 h after US exposure, while transgene expressions were significantly reduced in the presence of calcium channel blockers both in vitro and in vivo. CONCLUSIONS: Our results suggest that US enhanced PEI-mediated gene transfection specifically by increasing PKC-δ related fluid phase endocytosis, which was induced by increasing the intracellular calcium levels.

Stabilizing in vitro ultrasound-mediated gene transfection by regulating cavitation.

It is well known that acoustic cavitation can facilitate the inward transport of genetic materials across cell membranes (sonoporation). However, partially due to the unstationary behavior of the initiation and leveling of cavitation, the sonoporation effect is usually unstable, especially in low intensity conditions. A system which is able to regulate the cavitation level during sonication by modulating the applied acoustic intensity with a feedback loop is implemented and its effect on in vitro gene transfection is tested. The regulated system provided better time stability and reproducibility of the cavitation levels than the unregulated conditions. Cultured hepatoma cells (BNL) mixed with 10 µg luciferase plasmids are exposed to 1-MHz pulsed ultrasound with or without cavitation regulation, and the gene transfection efficiency and cell viability are subsequently assessed. Experimental results show that for all exposure intensities (low, medium, and high), stable and intensity dependent, although not higher, gene expression could be achieved in the regulated cavitation system than the unregulated conditions. The cavitation regulation system provides a better control of cavitation and its bioeffect which are crucial important for clinical applications of ultrasound-mediated gene transfection.

Control of inertial acoustic cavitation in pulsed sonication using a real-time feedback loop system.

Owing to the complex behavior of ultrasound-induced bubble clouds (nucleation, linear and nonlinear oscillations, collapse), acoustic cavitation remains a hardly controllable phenomenon, leading to poorly reproducible ultrasound-based therapies. A better control of the various aspects of cavitation phenomena for in vivo applications is a key requirement to improve emerging ultrasound therapies. Previous publications have reported on systems performing regulation of acoustic cavitation in continuous sonication when applied in vitro, but the main challenge today is to achieve real-time control of cavitation activity in pulsed sonication when used in vivo. The present work aims at developing a system to control acoustic cavitation in a pulsed wave condition using a real-time feedback loop. The experimental setup consists of a water bath in which is submerged a focused transducer (pulsed waves, frequency 550 kHz) used for sonication and a hydrophone used to listen to inertial cavitation. The designed regulation process allows the cavitation activity to be controlled through a 300 µs feedback loop. Without regulation, cavitation exhibits numerous bursts of intense activity and large variations of inertial cavitation level over time. In a regulated regime, the control of inertial cavitation activity within a pulse leads to consistent cavitation levels over time with an enhancement of the reproducibility.